circadian rhythm deregulation in patients with caps

Conditions: Cryopyrin Associated Periodic Syndrome; Familial Cold Urticaria; Muckle-Wells Syndrome; CINCA Syndrome

Summary: circadian rhythms are characterized by the physiology's adaptation to the alternation of day and night, enabling to adapt to the environment. these rhythms are generated by a molecular clock within each cell. at the molecular level, the circadian clock is based on a complex system of cell-autonomous transcription loops. these exert positive and negative feedback on themselves, generating cyclic transcriptional activity. * in the main loop, the bmal1 transcription factor links with clock or npas2 ( (neuronal pas domain protein 2) to activate transcription of per1,2 and 3 and cryptochrome (cry1 and cry2), which in turn repress bmal1/clock1 transcriptional activity.. the bmal1/clock complex also activates transcription of numerous target genes (per and cry, rev-erb, etc.).. * other secondary loops refine the function of the first. recent studies suggest that many aspects of innate immunity are controlled by circadian rhythm through inhibition of nlrp3 inflammasome activation. nevertheless, the regulation of the nlrp3 inflammasome by the circadian clock has yet to be elucidated. inflammasomes are molecular platforms that control caspase-1 activation and consequently the maturation of precursors of (interleukine) il-1β, pro-il-18, a pro-inflammatory cytokine. since its discovery, its functions have been widely characterized as part of the innate immune response as a sensor of pathogens and danger signals (extracellular atp (adenosine triphosphate), atmospheric pollutants). nlrp3 (nucleotide-binding domain lrr (leucin-rich repeat ) and pyrin-containing receptor 3) has been described for its genetic association with dominant monogenic hereditary syndromes characterized by recurrent systemic inflammatory episodes in the absence of any infection or autoimmune disease, known as caps (cryopyrin-associated periodic syndrome) or cryopyrinopathies which is a continuum of diseases ranging from a moderate to the most severe form of the syndrome: familial cold urticaria syndrome, muckle-wells syndrome (mws), and cinca/nomid syndrome. interestingly, patients with muckle-wells syndrome show a circadian pattern of symptoms, with a recurrent, predominantly vesperal fever peak lasting a few hours, and extreme fatigue on a daily basis. however, a molecular link between the circadian clock and caps pathology remains to be determined. the aim of this protocol is to identify circadian rhythm dysregulation in patients with caps confirmed by genetic analysis of nlrp3, to demonstrate a link between circadian clock and caps syndrome, and to identify circadian clock regulatory pathways.


Eligibility criteria:
---inclusion criteria: patient with caps group : * patients aged 6 and over * participant with caps confirmed by nlrp3 genetic analysis * weight greater than or equal to 25 kg * parents/guardians who have been informed of the study and have signed a consent form. * patient affiliated to a social security scheme control group (healthy participant): * participant aged 6 and over * weight greater than or equal to 25 kg * participant living in the same household as a subject with caps genetically confirmed by nlrp3 analysis and included in the protocol * participant with no caps (a priori) who consents to nlrp3 genetic analysis * parents/guardians who have been informed of the study and have signed a consent form. * participant who has been informed of the study and has agreed to take part * participant affiliated to a social security scheme * exclusion criteria : patient with caps group : * patients with chronic sleep disorders (narcolepsy, hypersomnia) requiring medication (sleeping pills, melatonin). * patients with sleep apnea syndrome * patients working regular night shifts or alternating day and night shifts * pregnant or breast-feeding women * parents with an infant under 6 months of age * patient participating in another interventional drug study * deprivation of civil rights (curators, guardianship, safeguard of justice) control group (healthy participant): * participants with a chronic illness (ald beneficiaries) * participants with chronic sleep disorders (narcolepsy, hypersomnia) requiring medication (sleeping pills, melatonin) * participants working regular night shifts or alternating day and night shifts * pregnant or breast-feeding women * parents with an infant under 6 months of age * participant participating in another interventional drug study * deprivation of civil rights (curators, guardianship, safeguard of justice)

Keywords: circadian clock cryopyrin-associated periodic syndrome familial cold urticaria muckle-wells syndrome melatonin